Media formulation optimization: current and future opportunities

Galbraith, Shaun; Bhatia, Hemlata; Liu, Yanling; Yoon, Seongkyu

doi:10.1016/j.coche.2018.08.004

Cited by 45 publications

(32 citation statements)

References 36 publications

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“…Current fed-batch mAb manufacturing platforms are durable and robust and have not yet fully matured (Bielser et al 2018;Croughan et al 2015;Kelley et al 2018;Yongky et al 2019). From the 1980s to the 2010s, manufacturing titers improved from tens of mg/L to ≥ 3 g/L by cell line engineering (Lin et al 2019;Wurm 2013), media development (Galbraith et al 2018;Huang et al 2010;, and process control improvements (Tang et al 2020;Xu et al 2019;Yoon et al 2003) achieving higher cell specific productivities, increased peak VCDs, and prolonged high productivity durations (Kunert and Reinhart 2016;Li et al 2010;Rader and Langer 2015;Wurm 2004). Higher titers continue to be reported in recent literature (e.g.…”

Section: Introductionmentioning

confidence: 99%

Development of an intensified fed-batch production platform with doubled titers using N-1 perfusion seed for cell culture manufacturing

Rehmann

et al. 2020

Bioresour. Bioprocess.

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The goal of cell culture process intensification is to increase volumetric productivity, generally by increasing viable cell density (VCD), cell specific productivity or production bioreactor utilization in manufacturing. In our previous study, process intensification in fed-batch production with higher titer or shorter duration was demonstrated by increasing the inoculation seeding density (SD) from ~ 0.6 (Process A) to 3-6 × 10 6 cells/mL (Process B) in combination with media enrichment. In this study, we further increased SD to 10-20 × 10 6 cells/mL (Process C) using perfusion N-1 seed cultures, which increased titers already at industrially relevant levels by 100% in 10-14 day bioreactor durations for four different mAb-expressing CHO cell lines. Redesigned basal and feed media were critical for maintaining higher VCD and cell specific productivity during the entire production duration, while medium enrichment, feeding strategies and temperature shift optimization to accommodate high VCDs were also important. The intensified Process C was successfully scaled up in 500-L bioreactors for 3 of the 4 mAbs, and quality attributes were similar to the corresponding Process A or Process B at 1000-L scale. The fed-batch process intensification strategies developed in this study could be applied for manufacturing of other mAbs using CHO and other host cells.

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Section: Introductionmentioning

confidence: 99%

Development of an intensified fed-batch production platform with doubled titers using N-1 perfusion seed for cell culture manufacturing

Rehmann

et al. 2020

Bioresour. Bioprocess.

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“…Bioprocess optimization of CHO cells has been a major topic of research, including studies which focused on the design of compositions of cell culture media (49, 50). Mammalian cell culture media are mostly composed of amino acids.…”

Section: Discussionmentioning

confidence: 99%

Systematically gap-filling the genome-scale metabolic model of CHO cells

Fouladiha

Marashi

et al. 2020

Preprint

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ObjectiveChinese hamster ovary (CHO) cells are the leading cell factories for producing recombinant proteins in the biopharmaceutical industry. In comparison to other mammalian cell types, in vitro handling of CHO cells is relatively easy. For example, CHO cells can grow in suspension and reach high cellular densities in bioreactors. Therefore, studying the metabolism of CHO cells to improve the bio-production of these cells is an important subject of research. In this regard, constraint-based metabolic models are useful platforms to perform computational analysis of cell metabolism.ResultsHere, we expanded the existing model of Chinese hamster metabolism (iCHO1766) with the help of four gap-filling approaches, leading to the addition of 773 new reactions and 335 new genes. We incorporated these into an updated genome-scale metabolic network model of CHO cells, named iCHO2101. This updated model substantially increased the number of reactions capable of carrying flux.ConclusionsThe addition of these new data provides an important step towards more complete metabolic models of CHO cells.

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“…Common approaches to develop a medium to optimize a phenotype of interest are often labor intensive, low throughput, or rely heavily on extensive analytical capacity (Galbraith, Bhatia, Liu, & Yoon, 2018). For example, analysis of residual media after cultivation requires extensive capabilities for analytical characterization and prior experience with the manufacturing host to identify potentially limiting or toxic media components (Mohmad-Saberi et al, 2013;Pereira, Kildegaard, & Andersen, 2018).…”

Section: Introductionmentioning

confidence: 99%

Modular development enables rapid design of media for alternative hosts

Biedermann

Gengaro

Rodriguez-Aponte

et al. 2021

Preprint

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Developing media to sustain cell growth and production is an essential and ongoing activity in bioprocess development. Modifications to media can often address host or product-specific challenges, such as low productivity or poor product quality. For other applications, systematic design of new media can facilitate the adoption of new industrially relevant alternative hosts. Despite manifold existing methods, common approaches for optimization often remain time and labor intensive. We present here a novel approach to conventional media blending that leverages stable, simple, concentrated stock solutions to enable rapid improvement of measurable phenotypes of interest. We applied this modular methodology to generate high-performing media for two phenotypes of interest: biomass accumulation and heterologous protein production, using high-throughput, milliliter-scale batch fermentations of Pichia pastoris as a model system. In addition to these examples, we also created a flexible open-source package for modular blending automation on a low-cost liquid handling system to facilitate wide use of this method. Our modular blending method enables rapid, flexible media development, requiring minimal labor investment and prior knowledge of the host organism, and should enable developing improved media for other hosts and phenotypes of interest.

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Media formulation optimization: current and future opportunities

Cited by 45 publications

References 36 publications

Development of an intensified fed-batch production platform with doubled titers using N-1 perfusion seed for cell culture manufacturing

Development of an intensified fed-batch production platform with doubled titers using N-1 perfusion seed for cell culture manufacturing

Systematically gap-filling the genome-scale metabolic model of CHO cells

Modular development enables rapid design of media for alternative hosts

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